Malaria
The Global Health Challenge
Ashley Kamiura & D. Scott Smith, M.D.
Stanford University
March 2013
Prepared as part of an education project of the
Global Health Education Consortium and collaborating partners
Learning Overview
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What Is Malaria?
History
Global Epidemiology: Key Facts
Vector Biology: Anopheles
Parasite Biology: Plasmodium
Transmission & The Life Cycle of
Plasmodium
Prevention
Millennium Development Goals
The Global Fight Against Malaria:
Major Players
Where Are We Right Now?
Quiz
Summary
2
What is Malaria?
3
What Is Malaria?
• Malaria is a disease caused by the
protozoan parasite Plasmodium.
There are 4 species of Plasmodium
that infect humans: P. falciparum, P.
ovale, P. malariae, and P. vivax.
• The parasite is transmitted to
humans via infected female
Anopheles mosquitoes.
• Symptoms include fever, chills, and
flu-like illness. If left untreated,
malaria can quickly become lifethreatening by disrupting the blood
supply to vital organs.
• Malaria is preventable and curable.
Photo (top): Lennart Nilsson – SCANPIX Sweden
Photo (bottom): Bill & Melinda Gates Foundation
Malaria parasites infect two red blood cells.
Mosquitoes feeding on a young boy’s hand and arm.
4
History
5
History
• 2700 BC: symptoms first described in ancient
Chinese medical writings.
• 340 CE: artemisinin drug discovered in Qinghao
plant in ancient China.
• In the New World, the Spanish learned of a
medicinal bark used to treat fevers. That medicine
is now known as the anti-malarial quinine.
• 1874: A German chemistry student synthesized
DDT (though its insecticidal properties were not
discovered until later).
Artemisia annua (Qinghao plant) at the
University of Oxford’s Botanic Garden
• 1880: Charles Laveran, a French army surgeon,
discovered parasites in the blood of a sick solider.
Awarded Nobel Prize in 1907 for this discovery.
Source: http://www.cdc.gov/malaria/history/index.htm
Photo: Claire Parfrey
6
History (cont)
• 1897: Ronald Ross, a British officer in the Indian
Medical Service, demonstrated that malaria
parasites could be transmitted from infected
patients to mosquitoes. He also showed that
mosquitoes could transmit the parasites from bird
to bird, demonstrating the existence of a
sporogonic cycle (development within the
mosquito). For his discovery, Ross was awarded
the Nobel Prize in 1902.
Charles Laveran
• 1899: Italian investigators demonstrated human
transmission by feeding mosquitoes on an
infected patient, then feeding them on two
uninfected volunteers, both of whom developed
malaria.
Ronald Ross
Source: http://www.cdc.gov/malaria/history/index.html
Photo: http://www.cdc.gov/malaria/history/
7
History (cont)
• 1906: Camillo Golgi, an Italian physician,
established the existence of multiple forms
of malaria based on fever periodicity and
cause of fevers. He was awarded the Nobel
Prize in 1906 for this discovery.
• 1934: Chloroquine was discovered in
Germany, though it wasn’t recognized as an
effective anti-malarial until 1946.
• 1939: The insecticidal properties of DDT
were discovered and used for malaria
control at the end of WWII. Its introduction
caused a huge decline in malaria (outside of
Africa) in the 1940s, but the development of
DDT resistance and its banishment caused a
resurgence in the 1970s.
Source: Centers For Disease Control and Prevention
Photo: Time Magazine archives
A vintage DDT ad printed in Time Magazine on June 30,
1947.
8
History (cont)
• 1951: Malaria was considered eliminated in
the U.S.
• 1955: The World Health Organization
submitted a proposal for the eradication of
malaria worldwide. Though some progress
has been made, barriers to success caused
the focus of the campaign to shift from
eradication to control. That effort
continues today.
Source: Centers For Disease Control And Prevention
9
Global Epidemiology: Key Facts
10
Global Epidemiology: Key Facts
• In 2010, malaria was endemic in 106 countries around the world:
Source: World Health Organization
11
Global Epidemiology: Key Facts (cont)
• In 2010, there were 24 million confirmed cases of
malaria and 325,000 deaths reported.
• However, because not all new cases nor deaths
are reported, it is estimated that 216 million
people became infected with malaria, while
655,000 people died from the disease. 174
million and 596,000, respectively, were in Africa
alone.
• More than 40% of 2010 malaria deaths occurred
in the Democratic Republic of Congo and Nigeria.
The countries with the next highest mortality
rates are Burkina Faso, Mozambique, Cote
d’Ivoire, and Mali.
• 86% of all malaria deaths in 2010 were in
children under 5 years of age.
Sources: Roll Back Malaria; World Malaria Report 2012
Photo: Bonnie Gillespie, Johns Hopkins University
12
Global Epidemiology: Key Facts (cont)
• Climate is the main determinant of malaria distribution.
• It is concentrated in tropical and subtropical areas due to temperature, humidity,
and rainfall patterns in these regions.
• Malaria distribution is a function of Anopheles’ survival. Anopheles’ eggs are
deposited in pools of standing water, where they develop into adulthood in 9-12
days.
• Temperature is also especially critical. P. falciparum
cannot complete its growth cycle within the
mosquito at temperatures below 20°C (68°F).
• Generally, in warmer regions near the equator,
transmission is more intense and occurs yearround.
• Global warming is expected to widen worldwide
malaria distribution.
Source: Centers For Disease Control And Prevention
Melting glaciers due to global warming.
13
Vector Biology: Anopheles
14
Vector Biology
• Anopheles is the only species of mosquito
that transmits malaria. There are 90 different
Anopheles species. Most are carriers but not
all.
• Only female Anopheles transmit malaria.
• Anopheles prefer to feed at night, typically
between dusk and dawn.
• Varied competence: some species carry few
parasites, others carry large numbers.
A female Anopheles albimanus mosquito engorged with
blood while feeding on a human host. Like other
Anopheles species, A. albimanus holds the major axis of
the body perpendicular to the surface of the skin when
blood feeding. This species is a common vector in Central
America.
Photo: James Gathany, Centers For Disease Control And Prevention, 2005
15
Vector Biology
• Global distribution of Anopheles species that act as a vector of malaria:
Source: Anthony Kiszewski, Andrew Mellinger, Andrew Spielman, Pia Malaney, Sonia Erlich Sachs, and Jeffrey
Sachs. A Global Index Representing The Stability of Malaria Transmission. Am J Trop Med Hyg 2004 70:486-498.
16
Vector Biology (cont)
• Some species of Anopheles prefer to remain
inside dwellings after feeding (endophilic),
while others prefer to rest outdoors
(exophilic).
• Some species prefer feeding indoors
(endophagic) while others prefer feeding
outdoors (exophagic).
• Some species prefer feeding on humans
(anthropophilic) while others prefer feeding
on animals (zoophilic).
A standing pool of water in Myanmar, Burma, a
potential mosquito breeding ground.
Photo: D. Scott Smith, July 2008.
• Generally, anthrophilic, endophagic
mosquitoes come into contact with humans
more frequently and are therefore more
effective vectors.
17
Parasite Biology: Plasmodium
18
Parasite Biology
• There are 5 different species of the
malaria parasite: Plasmodium vivax,
P. falciparum, P. ovale, P. malariae,
and P. knowlesii.
• The life cycles of P. vivax and P.
ovale include a dormant liver stage.
• P. vivax predominates in most parts
of the world.
• Infection with P. falciparum is the
most serious.
Anatomical view of the Plasmodium parasite.
Source: John, D.T. and W.A. Petri. 2006. Chapter 4: Malaria. Markell And Voge’s Medical Parasitology.
Photo: Wikipedia
19
Transmission & The Life Cycle of
Plasmodium
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Transmission & The Life Cycle of Plasmodium
• Transmission of the parasite occurs when an infected female mosquito feeds on
a human.
• The life cycle of Plasmodium (see Supplementary Note on next page) is as
follows:
Photo: www.biology-forums.com
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21
Supplementary Note: The Life Cycle of Plasmodium
Malaria parasites are spread by infecting two hosts: humans and female Anopheles
mosquitoes.
If an uninfected mosquito feeds on an infected human, she will take in blood containing
male and female gametocytes. The gametocytes will then mature inside the mosquito
and undergo sexual reproduction to form a zygote, which after passing through several
developmental stages, eventually results in the production of a large number of
sporozoites (“sporogony”). The sporozoites wander throughout the body of the
mosquito, including the salivary glands, where they will be inoculated into the next
person on which she feeds.
In humans, the parasites leave the blood vascular system and invade the parenchymal
cells of the liver, where they undergo asexual multiplication (“shizogony”). Rupture of
the hepatic cells releases merozoites into the circulation, where they can then invade red
blood cells (RBCs). In RBCs, the parasites continue to divide and cause the cells to burst,
releasing merozoites that continue the cycle and invade other RBCs. This stage of the life
cycle causes symptoms of chills and fever in the infected individual. Merozoites develop
into gametocytes within RBCs, where they can be ingested by a feeding mosquito.
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Prevention
23
Prevention
• Key interventions to control malaria include bed nets, insecticides, and drugs.
• Long lasting insecticide treated bed nets (LLINs)
– Provide a physical barrier between humans and mosquitoes during the time
of day mosquitoes are most likely to transmit malaria – at night.
– Cost per person for one year of protection by an LLIN: $1.39 USD.
– Spraying this imperfect barrier with insecticide will kill a mosquito before it
can find a way past the net.
– For
F
maximum effectiveness,
regular bed nets must be retreated with insecticide every 6
months. Due to the logistical
infeasibility of this requirement
in rural areas, LLINs were
developed and can provide
protection for up to 5 years.
Source: Roll Back Malaria Campaign
Photo: Antonio Matimbe/World Vision
Children sit under an LLIN in Ghana.
24
Prevention
•
Artemesinin-Based Combination Therapy (ACT)
– The current course of treatment for malaria-infected individuals.
– Cost of single adult course of ACT treatment: $0.90 - $1.40 USD.
– Cost of single child course of ACT treatment: $0.30 - $0.40 USD.
– Resistance has been detected in 4 countries in Southeast Asia.
– Effective and well-tolerated by patients, but due to high cost, patients often
purchase cheaper, less effective, poor quality, or counterfeit drugs, leading to ACTresistant strains of Plasmodium.
•
Indoor Residual Spraying (IRS)
– The spraying of insecticides on the interior
walls of dwellings.
– WHO currently advises the use of 12 different
insecticides, including DDT, permethrin, and
deltamethrin.
– Mosquito resistance to insecticides has been
detected in 64 countries.
Source: Roll Back Malaria Campaign; World Malaria Report 2012
Photo: Agfax
Indoor residual spraying in Ethiopia.
25
Prevention
• Rapid Malaria Diagnostic Tests (RDTs)
– A.K.A. “Dipsticks,” assist in the diagnosis of malaria by providing evidence of
the presence of the parasite in the blood obtained from a finger prick.
– Cost for a single RDT: $0.50 USD.
– Work by detecting specific antigens produced by the parasite.
– A reliable alternative to diagnosis by microscopy when microscopy not
readily available.
• Malaria Vaccine
– Currently, there is no vaccine to prevent malaria, but this is an active field of
research.
– In recent Phase III clinical trials, the RTS,S vaccine had lower-than-desired
efficacy, but the trials did prove it is possible to vaccinate against a parasite.
– Current vaccine candidates target specific groups. Ultimately, more
efficacious second-generation vaccines that can protect entire populations
will be required.
Sources: Roll Back Malaria Campaign; The Bill & Melinda Gates Foundation
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Millennium Development Goals
27
Millennium Development Goals
• In September 2000, all 191 member countries of the United Nations signed the
Millennium Declaration, which contained eight goals surrounding poverty,
hunger, disease, illiteracy, environmental degradation, and discrimination
against women. The target date for achieving these Millennium Development
Goals is 2015.
• Millennium Development Goal 6C is “to have halted by 2015 and begun to
reverse incidence of malaria and other major diseases.”
• In a 2007 resolution, the World
Health Assembly defined this reversal
of malaria incidence as a 75%
reduction of the global malaria
burden.
• Who is working to achieve this goal?
Source: World Health Organization
28
The Global Fight Against Malaria:
Major Players
29
The Global Fight Against Malaria – Major Players
The Bill & Melinda Gates Foundation (B&MGF)
• Long term goal is to eradicate the disease
• Approach includes:
•
–
Developing a preventive malaria vaccine by 2025
that will be safe for children and pregnant mothers
–
Developing more effective drugs and diagnostics
that are cheaper for people of poor countries
–
Developing new tools to control mosquitoes,
including looking into new active ingredients and
products that combat insecticide resistance
–
Research the effectiveness of malaria
interventions, including delivery methods
In 2011 alone, awarded $200M in grants
supporting malaria eradication efforts
Source: The Bill & Melinda Gates Foundation
Photo: Larry Hollon
Bill and Melinda Gates being interviewed at the 2011
Malaria Forum.
30
The Global Fight Against Malaria – Major Players (cont)
The Bill & Melinda Gates Foundation (B&MGF)
• Among numerous other grants, in 2012 the B&MGF awarded:
–
$1.5M to the Malaria Consortium to develop a sustainable community delivery model of
Seasonal Malaria Chemoprevention.
–
$3M to WHO to establish a “situation room” to assist the 10 sub-Saharan Africa countries
with the highest number of malaria cases and deaths. The situation room will work to
resolve bottlenecks in financing, supply, scale up of interventions, and public health
impacts.
–
$7.7M to the Harvard School of Public Health to develop
diagnostic tools using genotyping and sequencing
technologies, based on the population genetics of malaria
parasites.
–
$5M to the Menzies School of Health Research for research
on the safe, global deployment of the drug primaquine and
the radical cure of P. vivax.
–
$750M to the Global Fund to Fight AIDS, Tuberculosis, and
Source: The Bill & Melinda Gates Foundation
Malaria.
Photo: Forbes
Bill Gates holding an infant girl in
Tanzania.
31
The Global Fight Against Malaria – Major Players (cont)
The Global Fund to Fight AIDS, Tuberculosis, and Malaria (GF)
• An international financing institution dedicated to attracting and disbursing
resources to preventing and treating the world’s three most deadliest
diseases.
• Holds grant recipients accountable to strict standards that require specific
targets to be reached throughout the life of the grant.
• Channels 50% of the global funding for malaria.
• Since its inception in 2002, the GF has provided 310 million bed nets,
provided IRS in 44 million dwellings, and has financed ACT treatment for 260
million cases.
Source: The Global Fund
32
The Global Fight Against Malaria – Major Players (cont)
World Health Organization (WHO)
• Administers the Global Malaria Programme (GMP), which convenes experts to
review evidence and set global policies, providing the benchmark for
international malaria programs and multilateral funding agencies.
Source: World Health Organization
33
The Global Fight Against Malaria – Major Players (cont)
Roll Back Malaria (RBM)
• The RBM partnership was launched in 1998 by WHO, UNICEF, UNDP, and the
World Bank in an effort to provide a coordinated global response to the
disease.
• RBM’s vision is a world free from the burden of malaria.
• At the MDG Malaria Summit in September 2008, world leaders and the
global malaria community gathered in New York to endorse the Global
Malaria Action Plan (GMAP), which provides a global framework for action
around which partners can coordinate their efforts in meeting the 2015
MDGs.
“I believe that if you show people a problem, and then you show them the solution, they will
be moved to act. The Global Malaria Action Plan lays out an achievable blueprint for fighting
malaria – now it’s time for the world to take action.”
– Bill Gates, Co-Chair, Bill & Melinda Gates Foundation
Source: Roll Back Malaria Campaign
34
Where Are We Right Now?
35
Where Are We Right Now?
• The past 5 years have seen an impressive
increase in international funding for malaria
control efforts.
• Over the past decade, an estimated 1.1M
malaria deaths were averted as a result.
• 50 countries are currently on track to reduce
their malaria incidence rates by 75%, in line
with the Roll Back Malaria Campaign’s
targets for 2015.
• However, these 50 countries account for
only 3% of the total estimated malaria cases
worldwide.
A young girl holds a “malaria” sign.
Source: World Malaria Report 2012
Photo: www.futurity.org
36
Where Are We Right Now?
• International targets will not be met unless
considerable progress is made in the 14 countries
with the highest malaria burden, which account
for an estimated 80% of malaria deaths.
• Unfortunately, current funding falls short of what
is needed to reach the Millennium Development
Goals by 2015. An estimated $5.1B USD is
required each year between 2011 and 2020 to
achieve universal access to malaria interventions .
• Presently, only $2.3B USD is available.
• We have come a long way in the fight against
malaria since 1955, but to reach the Millennium
Development Goals new funding sources must be
identified to further scale up and sustain current
efforts.
Source: World Malaria Report 2012
37
Quiz
See if you can answer the following 8 questions.
Each question is followed by the correct
answer, shown in green.
38
What are some challenges faced by malaria vaccine
developers?
a) Antigens produced by the parasite differ depending on the life
cycle stage it is currently in
b) Attenuated parasites sometimes exhibit abnormal behavior, such
as an inability to enter hepatocytes
c) Evidence of resistance to artemesinin
d) Logistical obstacles to administering a vaccine to the general public
e) All of the above
39
What are some challenges faced by malaria vaccine
developers?
a) Antigens produced by the parasite differ depending on the life
cycle stage it is currently in
b) Attenuated parasites sometimes exhibit abnormal behavior, such
as an inability to enter hepatocytes
c) Evidence of resistance to artemesinin
d) Logistical obstacles to administering a vaccine to the general public
e) All of the above
40
In which region of the world do the most deaths
from malaria occur each year?
a) China and India, the two most populous countries
b) Southeast Asia, where resistance to anti-malarial drugs most
commonly occurs
c) Sub-Saharan Africa
d) South America, which contains the Amazon and abundant standing
pools of water
e) The US and Europe, where the most cases are positively diagnosed
41
In which region of the world do the most deaths
from malaria occur each year?
a) China and India, the two most populous countries
b) Southeast Asia, where resistance to anti-malarial drugs most
commonly occurs
c) Sub-Saharan Africa
d) South America, which contains the Amazon and abundant standing
pools of water
e) The US and Europe, where the most cases are positively diagnosed
42
The malaria parasite is transmitted by which
vector?
a)
b)
c)
d)
e)
Reduvid bugs
Aedes mosquitos
Culex mosquitos
Any blood sucking insect
Anopheles mosquitos
43
The malaria parasite is transmitted by which
vector?
a)
b)
c)
d)
e)
Reduvid bugs
Aedes mosquitos
Culex mosquitos
Any blood sucking insect
Anopheles mosquitos
44
A mosquito that bites a human indoors then rests
outdoors is:
a)
b)
c)
d)
e)
Zoophilic, endophagic, endophilic
Zoophilic, endophagic, exophilic
Anthrophilic, endophagic, endophilic
Anthrophilic, endophagic, exophilic
Anthrophilic, exophagic, endophilic
45
A mosquito that bites a human indoors then rests
outdoors is:
a)
b)
c)
d)
e)
Zoophilic, endophagic, endophilic
Zoophilic, endophagic, exophilic
Anthrophilic, endophagic, endophilic
Anthrophilic, endophagic, exophilic
Anthrophilic, exophagic, endophilic
46
What is an environmental condition that may
prevent the transmission of malaria?
a)
b)
c)
d)
e)
High altitude
Heat
Desert oases containing water
Availability of animal reservoirs
Global warming
47
What is an environmental condition that may
prevent the transmission of malaria?
a)
b)
c)
d)
e)
High altitudes
Heat
Desert oases containing water
Availability of animal reservoirs
Global warming
48
Public health strategies proven to effectively
control malaria include all of the following except:
a) Spraying the interior walls of dwellings with insecticides
b) Distributing mesh nets treated with insecticides meant for sleeping
under
c) Releasing genetically incompetent vectors in areas of high
transmission rates
d) Surveillance and treatment with anti-malarial drugs
e) Targeting mosquito larva for control
49
Public health strategies proven to effectively
control malaria include all of the following except:
a) Spraying the interior walls of dwellings with insecticides
b) Distributing mesh nets treated with insecticides meant for sleeping
under
c) Releasing genetically incompetent vectors in areas of high
transmission rates
d) Surveillance and treatment with anti-malarial drugs
e) Targeting mosquito larva for control
50
Since 2008, funding for malaria control efforts has
steadily increased.
a) True
b) False
51
Since 2008, funding for malaria control efforts has
steadily increased.
a) True
b) False
52
The following terms are applicable to categorizing
malaria control efforts except:
a)
b)
c)
d)
e)
Control
Pre-elimination
Eradication
Elimination
Prevention of re-introduction
53
The following terms are applicable to categorizing
malaria control efforts except:
a)
b)
c)
d)
e)
Control
Pre-elimination
Eradication
Elimination
Prevention of re-introduction
54
Summary
• Malaria is a parasite that is transmitted to humans via infected
mosquitoes.
• Malaria is preventable and curable. However, if left untreated,
malaria can cause death by disrupting the blood supply to organs.
• It was first described in Chinese antiquity but has more recently
been understood biologically using microscopes.
• The world’s heaviest malaria burden is in Africa. 40% of all malaria
deaths in 2010 were in four African countries alone.
• Children under the age of 5 are the demographic most affected by
malaria. In 2010, 86% of all malaria deaths occurred in children
under 5 years of age.
55
Summary (cont)
• The world’s heaviest malaria burden is in Africa. 40% of all malaria
deaths in 2010 were in four African countries alone.
• The distribution of malaria is a function of Anopheles survival,
which is in turn a function of climate. Anopheles requires warm
climates to survive. It follows, then, that malaria prevalence is
highest in warmer areas near the equator, though global warming
is expected to increase the lateral ranges of global malaria
distribution.
• Only female Anopheles mosquitoes transmit malaria.
• There are five different species of the malaria parasite.
Plasmodium falciparum is the most serious.
56
Summary (cont)
• Key interventions to malaria transmission include bed nets,
insecticides, and drugs.
• Currently, no vaccine against malaria exists, though this is an active
area of research.
• The Millennium Development Goals call for a reversal of the global
malaria burden by 75% by 2015.
• Several organizations, including The Bill & Melinda Gates
Foundation, The Global Fund, the World Health Organization, and
the Roll Back Malaria Campaign.
57
Summary (cont)
• Since 2008, there has been an impressive increase in funding for
malaria control efforts, and 1.1M malaria deaths were averted as a
result. 50 countries are currently on track to meet the Millennium
Development Goals.
• However, additional funding is required in order to meet these
internationally agreed upon targets. Specifically, $5.1B per year is
required between 2011 and 2020, but only $2.3B is currently
available.
58
References
Papers
Garner P, Systematic reviews in malaria: global policies need global reviews. Infect Dis Clin North Am - 01JUN-2009; 23(2): 387-404.
Kiszewski, A., A Mellinger, A Spielman, P Malaney, SE Sachs, and J Sachs. A Global Index Representing The
Stability of Malaria Transmission. Am J Trop Med Hyg 2004 70:486-498.
Medicine: Knockout malaria vaccine?, Ménard, R., Medicine: Knockout malaria vaccine? Nature 433, 113114 (13 January 2005)
Mishra SK, Mohanty S, Mohanty A, Das BS. Management of severe and complicated malaria. J Postgrad
Med. 2006 Oct-Dec;52(4):281-7.
Books
John, D.T. and W.A. Petri. 2006. Chapter 4: Malaria. Markell And Voge’s Medical Parasitology. St Louis:
Saunders Elsevier, pp. 79-106.
Mandell, G.L., J.E. Bennett and R. Dolin. 2010. Chapter 275: Plasmodium Species (Malaria). Principles and
Practice of Infectious Diseases, 7th Edition. Churchhill Livingstone Elsevier, pp. 3437-3462.
59
References (cont)
Websites
• Bill & Melinda Gates Foundation: http://www.gatesfoundation.org/What-We-Do/GlobalHealth/Malaria
• Centers For Disease Control and Prevention: http://www.cdc.gov/MALARIA/
• Roll Back Malaria: http://www.rbm.who.int/
• The Global Fund To Fight AIDS, Tuberculosis, and Malaria:
http://www.theglobalfund.org/en/
• World Health Organization (World Malaria Report 2012):
http://www.who.int/topics/malaria/en/
60
Credits
• Ashley Kamiura, BA, Stanford University
• [email protected]
• D. Scott Smith, MD, MSc, DTM&H
• Chief of Infectious Disease & Geographic Medicine,
Kaiser Permanente, Redwood City, California
• Adjunct Assistant Clinical Professor
Depts. of Human Biology and Medical Microbiology
& Immunology, Stanford University School of
Medicine
• [email protected]
61
The Global Health Education Consortium and the Consortium of
Universities for Global Health gratefully acknowledge the support
provided for developing teaching modules from the:
Margaret Kendrick Blodgett Foundation
The Josiah Macy, Jr. Foundation
Arnold P. Gold Foundation
This work is licensed under a
Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 United States
License.
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